PROJECT SUMMARY/ABSTRACT A positive family history of alcoholism (FHP) is a well-established risk factor for the development of alcohol use disorders (AUD). This vulnerability is multifaceted as it is associated with several individual risk factors such as impaired cognitive control and a low level of response (LR) to the effects of alcohol. Cognitive control is an essential aspect of executive function that allows individuals to flexibly respond to changing environmental demands by integrating past experiences with current goal-directed behavior. Neuroimaging evidence indicates that effective cognitive control relies on activation of the lateral and medial prefrontal cortices (PFC) and functional connectivity between regions. Though limited, evidence from both neurophysiological and hemodynamic methods indicates alterations in neural activation patterns and functional connectivity in FHP individuals. Impaired cognitive control is heavily implicated in the development of AUD through diminished self- regulation of alcohol consumption. In addition to cognitive control deficits, FHP exhibit a low LR to the subjective effects of alcohol, requiring greater amounts to feels similar effects as individuals without a family history. Importantly, acute alcohol intoxication selectively attenuates activation of the lateral and medial PFC, which may contribute to impulsively drinking more than intended. Few studies, however, have examined how the effects of alcohol on the neural circuitry subserving cognitive control are influenced by FHP. Therefore, the overall aim of this proposal is to characterize the neural indices of cognitive control and their sensitivity to the effects of alcohol, as well as the functional connectivity of the underlying network, in FHP individuals compared to a matched group of individuals with no family history of alcoholism. The proposed project will use a multimodal imaging approach with two main aims: (1) use an anatomically-constrained magnetoencephalography (aMEG) method to examine the effects of alcohol intoxication on theta oscillations and long-range co-oscillations in FHP individuals during a cognitively demanding task such as the Stroop task and (2) characterize the neurofunctional network underlying cognitive control as a function of a family history of alcoholism using MRI-based functional connectivity (fcMRI). The aMEG method combines the temporal precision of MEG and the spatial mapping of structural MRI making it possible to examine the effects of alcohol on theta oscillations and co-oscillations. Event-related theta oscillations are sensitive to cognitive effort while co-oscillations integrate neural communication between cortical regions during cognitive control. As a complementary method, the spatial mapping of fcMRI can be used to examine inherent differences in connectivity between regions within a neurofunctional network. The multimodal approach using both aMEG and fcMRI will provide insight into the neural indices of cognitive control and their sensitivity to alcohol intoxication in individuals with a family history of alcoholism. These findings could help elucidate the neurobiological contributions that increase the risk for FHP individuals to develop AUD.